Vivekanandan Ramalingam
Basic Life Research Scientist, Genetics
All Publications
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An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
PloS one
2025; 20 (3): e0318796
Abstract
In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
View details for DOI 10.1371/journal.pone.0318796
View details for PubMedID 40163815
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An Expanded Registry of Candidate cis-Regulatory Elements for Studying Transcriptional Regulation.
bioRxiv : the preprint server for biology
2024
Abstract
Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression. Previously, The ENCODE consortium mapped biochemical signals across many cell types and tissues and integrated these data to develop a Registry of 0.9 million human and 300 thousand mouse candidate cis-Regulatory Elements (cCREs) annotated with potential functions1. We have expanded the Registry to include 2.35 million human and 927 thousand mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded Registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays like STARR-seq, MPRA, CRISPR perturbation, and transgenic mouse assays now cover over 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer/silencer roles in different cellular contexts. Integrating the Registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by discovering KLF1 as a novel causal gene for red blood cell traits. This expanded Registry is a valuable resource for studying the regulatory genome and its impact on health and disease.
View details for DOI 10.1101/2024.12.26.629296
View details for PubMedID 39763870
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Deciphering the impact of genomic variation on function.
Nature
2024; 633 (8028): 47-57
Abstract
Our genomes influence nearly every aspect of human biology-from molecular and cellular functions to phenotypes in health and disease. Studying the differences in DNA sequence between individuals (genomic variation) could reveal previously unknown mechanisms of human biology, uncover the basis of genetic predispositions to diseases, and guide the development of new diagnostic tools and therapeutic agents. Yet, understanding how genomic variation alters genome function to influence phenotype has proved challenging. To unlock these insights, we need a systematic and comprehensive catalogue of genome function and the molecular and cellular effects of genomic variants. Towards this goal, the Impact of Genomic Variation on Function (IGVF) Consortium will combine approaches in single-cell mapping, genomic perturbations and predictive modelling to investigate the relationships among genomic variation, genome function and phenotypes. IGVF will create maps across hundreds of cell types and states describing how coding variants alter protein activity, how noncoding variants change the regulation of gene expression, and how such effects connect through gene-regulatory and protein-interaction networks. These experimental data, computational predictions and accompanying standards and pipelines will be integrated into an open resource that will catalyse community efforts to explore how our genomes influence biology and disease across populations.
View details for DOI 10.1038/s41586-024-07510-0
View details for PubMedID 39232149
View details for PubMedCentralID 7405896
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An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
bioRxiv : the preprint server for biology
2024
Abstract
In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
View details for DOI 10.1101/2024.06.04.597442
View details for PubMedID 38895386
View details for PubMedCentralID PMC11185660
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Lola-I is a promoter pioneer factor that establishes de novo Pol II pausing during development.
Nature communications
2023; 14 (1): 5862
Abstract
While the accessibility of enhancers is dynamically regulated during development, promoters tend to be constitutively accessible and poised for activation by paused Pol II. By studying Lola-I, a Drosophila zinc finger transcription factor, we show here that the promoter state can also be subject to developmental regulation independently of gene activation. Lola-I is ubiquitously expressed at the end of embryogenesis and causes its target promoters to become accessible and acquire paused Pol II throughout the embryo. This promoter transition is required but not sufficient for tissue-specific target gene activation. Lola-I mediates this function by depleting promoter nucleosomes, similar to the action of pioneer factors at enhancers. These results uncover a level of regulation for promoters that is normally found at enhancers and reveal a mechanism for the de novo establishment of paused Pol II at promoters.
View details for DOI 10.1038/s41467-023-41408-1
View details for PubMedID 37735176
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The dynseq browser track shows context-specific features at nucleotide resolution.
Nature genetics
2022
View details for DOI 10.1038/s41588-022-01194-w
View details for PubMedID 36241719
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Acquisition of innate odor preference depends on spontaneous and experiential activities during critical period.
eLife
2021; 10
Abstract
Animals possess an inborn ability to recognize certain odors to avoid predators, seek food and find mates. Innate odor preference has been thought to be genetically hardwired. Here we report that acquisition of innate odor recognition requires spontaneous neural activity and is influenced by sensory experience during early postnatal development. Genetic silencing of mouse olfactory sensory neurons during the critical period has little impact on odor sensitivity, discrimination, and recognition later in life. However, it abolishes innate odor preference and alters the patterns of activation in brain centers. Moreover, exposure to an aversive odor during the critical period abolishes aversion in adulthood in an odor-specific manner. The loss of innate aversion is associated with broadened projection of OSNs. Thus, a delicate balance of neural activity is required during the critical period in establishing innate odor preference and ectopic projection is a convergent mechanism to alter innate odor valence.
View details for DOI 10.7554/eLife.60546
View details for PubMedID 33769278
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TATA and paused promoters active in differentiated tissues have distinct expression characteristics
MOLECULAR SYSTEMS BIOLOGY
2021; 17 (2): e9866
Abstract
Core promoter types differ in the extent to which RNA polymerase II (Pol II) pauses after initiation, but how this affects their tissue-specific gene expression characteristics is not well understood. While promoters with Pol II pausing elements are active throughout development, TATA promoters are highly active in differentiated tissues. We therefore used a genomics approach on late-stage Drosophila embryos to analyze the properties of promoter types. Using tissue-specific Pol II ChIP-seq, we found that paused promoters have high levels of paused Pol II throughout the embryo, even in tissues where the gene is not expressed, while TATA promoters only show Pol II occupancy when the gene is active. The promoter types are associated with different chromatin accessibility in ATAC-seq data and have different expression characteristics in single-cell RNA-seq data. The two promoter types may therefore be optimized for different properties: paused promoters show more consistent expression when active, while TATA promoters have lower background expression when inactive. We propose that tissue-specific genes have evolved to use two different strategies for their differential expression across tissues.
View details for DOI 10.15252/msb.20209866
View details for Web of Science ID 000624493600002
View details for PubMedID 33543829
View details for PubMedCentralID PMC7863008